Alex F. Chen

1. Curcumin is a naturally occurring poly-phenolic compound with a broad range of favourable biological functions, including anti-cancer, anti-oxidant and anti-inflammatory activities. The low bioavailability and in vivo stability of curcumin require the development of suitable carrier vehicles to deliver the molecule in a sustained manner at therapeutic levels. 2. In the present study, we investigated the feasibility and potential of poly(caprolactone) (PCL) nanofibres as a delivery vehicle for curcumin for wound healing applications. By optimizing the electrospinning parameters, bead-free curcumin-loaded PCL nanofibres were developed. 3. The fibres showed sustained release of curcumin for 72 h and could be made to deliver a dose much lower than the reported cytotoxic concentration while remaining bioactive. Human foreskin fibroblast cells (HFF-1) showed more than 70% viability on curcumin-loaded nanofibres. 4. The anti-oxidant activity of curcumin-loaded nanofibres was demonstrated using an oxygen radical absorbance capacity (ORAC) assay and by the ability of the fibres to maintain the viability of HFF-1 cells under conditions of oxidative stress. 5. The curcumin-loaded nanofibres also reduced inflammatory induction, as evidenced by low levels of interleukin-6 release from mouse monocyte-macrophages seeded onto the fibres following stimulation by Escherichia coli-derived lipopolysaccharide. 6. The in vivo wound healing capability of the curcumin loaded PCL nanofibres was demonstrated by an increased rate of wound closure in a streptozotocin-induced diabetic mice model. 7. These results demonstrate that the curcumin-loaded PCL nanofibre matrix is bioactive and has potential as a wound dressing with anti-oxidant and anti-inflammatory properties.

BACKGROUND: Molecular descriptors and fingerprints have been routinely used in QSAR/SAR analysis, virtual drug screening, compound search/ranking, drug ADME/T prediction and other drug discovery processes. Since the calculation of such quantitative representations of molecules may require substantial computational skills and efforts, several tools have been previously developed to make an attempt to ease the process. However, there are still several hurdles for users to overcome to fully harness the power of these tools. First, most of the tools are distributed as standalone software or packages that require necessary configuration or programming efforts of users. Second, many of the tools can only calculate a subset of molecular descriptors, and the results from multiple tools need to be manually merged to generate a comprehensive set of descriptors. Third, some packages only provide application programming interfaces and are implemented in different computer languages, which pose additional challenges to the integration of these tools. RESULTS: A freely available web-based platform, named ChemDes, is developed in this study. It integrates multiple state-of-the-art packages (i.e., Pybel, CDK, RDKit, BlueDesc, Chemopy, PaDEL and jCompoundMapper) for computing molecular descriptors and fingerprints. ChemDes not only provides friendly web interfaces to relieve users from burdensome programming work, but also offers three useful and convenient auxiliary tools for format converting, MOPAC optimization and fingerprint similarity calculation. Currently, ChemDes has the capability of computing 3679 molecular descriptors and 59 types of molecular fingerprints. CONCLUSION: ChemDes provides users an integrated and friendly tool to calculate various molecular descriptors and fingerprints. It is freely available at http://www.scbdd.com/chemdes. The source code of the project is also available as a supplementary file. Graphical abstract:An overview of ChemDes. A platform for computing various molecular descriptors and fingerprints.

BACKGROUND: Essential hypertension has been recognized as a disease resulting from a combination of environmental and genetic factors. Recent studies demonstrated that microRNAs (miRNAs) are involved in cardiac hypertrophy and heart failure. However, little is known about the roles of miRNAs in essential hypertension. METHODS AND RESULTS: Using microarray-based miRNA expression profiling, we compared the miRNA expressions in plasma samples from 13 hypertensive patients and 5 healthy control subjects. Twenty-seven miRNAs were found to be differentially expressed. The expressions of selected miRNAs (miR-296-5p, let-7e, and a human cytomegalovirus [HCMV]-encoded miRNA, hcmv-miR-UL112) were validated independently in plasma samples from 24 hypertensive patients and 22 control subjects. The absolute expression levels of hcmv-miR-UL112, miR-296-5p, and let-7e were further determined in 127 patients and 67 control subjects (fold changes are 2.5, 0.5, and 1.7 respectively; all P<0.0001). Additionally, we demonstrated that interferon regulatory factor 1 is a direct target of hcmv-miR-UL112. Increased HCMV seropositivity and quantitative titers were found in the hypertension group compared with the control group (52.7% versus 30.9%, P=0.0005; 1870 versus 54 copies per 1 mL plasma, P<0.0001). Seropositivity, log-transformed copies of HCMV, and hcmv-miR-UL112 were independently associated with an increased risk of hypertension (odds ratio, 2.48; 95% confidence interval, 1.48 to 4.15; P=0.0005; odds ratio, 1.97; 95% confidence interval, 1.58 to 2.46; P<0.0001; and odds ratio, 2.55; 95% confidence interval, 1.98 to 3.27; P<0.0001, respectively). CONCLUSIONS: We report for the first time a circulating miRNA profile for hypertensive patients and demonstrate a novel link between HCMV infection and essential hypertension. These findings may reveal important insights into the pathogenesis of essential hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00420784.

Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. However, the role of miR-34a in EPC-mediated angiogenesis was unknown. The present study tested the hypothesis that miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1. Bone marrow-derived EPCs from adult male Sprague-Dawley rats were used. Results of flow cytometry showed that EPCs after 7 days of culture expressed both stem cell markers CD34 and CD133 and endothelial cell markers VEGFR-2 (flk-1) and VE-cadherin. MiR-34a was expressed in normal EPCs, and overexpression of miR-34a via its mimic transfection significantly increased its expression and impaired in vitro EPC angiogenesis. MiR-34a overexpression led to a significantly increased EPC senescence, paralleled with an approximately 40% Sirt1 reduction. Furthermore, knockdown of Sirt1 by its siRNA resulted in diminished EPC angiogenesis and increased senescence. Finally, overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1), an effect mimicked in EPCs following Sirt1 knockdown. In conclusion, miR-34a impairs EPC-mediated angiogenesis by induction of senescence via inhibiting Sirt1.